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Sorafenib Tosylate in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2017 by Roswell Park Cancer Institute
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Roswell Park Cancer Institute Identifier:
First received: February 24, 2014
Last updated: April 13, 2017
Last verified: April 2017
This clinical trial studies sorafenib tosylate in treating patients with liver cancer that cannot be removed by surgery. Sorafenib tosylate may block some of the enzymes needed for tumor cell growth. Blocking these enzymes may also help the immune system work better. Granzyme B is a biomarker that can be used to measure how well the immune system is working. A biomarker is a biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. Studying granzyme B levels in patients receiving sorafenib tosylate may help doctors learn more about the effects of sorafenib tosylate on the immune system and may help to predict how well sorafenib tosylate will work in treating patients with liver cancer.

Condition Intervention
Advanced Adult Hepatocellular Carcinoma
Localized Non-Resectable Adult Hepatocellular Carcinoma
Stage III Childhood Hepatocellular Carcinoma
Stage IIIA Hepatocellular Carcinoma
Stage IIIB Hepatocellular Carcinoma
Stage IIIC Hepatocellular Carcinoma
Stage IV Childhood Hepatocellular Carcinoma
Stage IVA Hepatocellular Carcinoma
Stage IVB Hepatocellular Carcinoma
Other: Laboratory Biomarker Analysis
Drug: Sorafenib Tosylate

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Granzyme B Production as a Biomarker for the Immunomodulatory Activity of Sorafenib in HCC

Resource links provided by NLM:

Further study details as provided by Roswell Park Cancer Institute:

Primary Outcome Measures:
  • Granzyme B levels [ Time Frame: Up to 35 days ]
    The pGrzB hazard ratio (per 10 percentage point increase) and the associated 95% confidence interval will be estimated using a Cox PH model. Whether pGrzB measurements vary by presence of grade 3+ adverse events (AEs) will be assessed using permutation independent sample t-tests. Descriptive statistics include the pGrzB mean, standard deviations and ranges within AE or patient characteristics.

  • Overall survival (OS) [ Time Frame: Time between start of first treatment and death, assessed up to 6 months ]
    The hazard ratio and 95% confidence interval for the effect of day ~28-35 pGrzB (in 10 percentage point increments) on OS will be estimated using proportional hazards (PH) models. The pGrzB functional form will be assessed using generalized additive models. Possible confounding from sorafenib dose differences and baseline characteristics will be assessed by including other covariates (or perhaps frailty terms) in the model.

Secondary Outcome Measures:
  • Granzyme B level variations by presence of grade 3 or higher AE, characterized using National Cancer Institute Common Terminology Criteria for Adverse Events severity grade [ Time Frame: Up to 30 days ]
    These differences will be assessed using permutation independent sample t-tests. For an AE observed in 15 (50%) of the patients and two-sided statistical significance threshold = 0.05, this test has 80% power to detect a 1.0 standard difference in mean pGrzB. 95% confidence limits for the difference in mean pGrzB will also be provided. Descriptive statistics include the pGrzB mean, standard deviations and ranges within AE or patient characteristics.

Other Outcome Measures:
  • Change in granzyme B levels after sorafenib tosylate treatment [ Time Frame: Baseline to up to 35 days ]
    The hypotheses of immediate (HI) and sustained improvement (HS) of immune function will be tested using a fixed-sequence procedure. Each hypothesis uses a permutation paired t-test with an upper 1-sided 0.05 significance threshold. HI considers a pGrzB increase between days 0 & ~28-35. If the HI test finds no short-term pGrzB improvement, the HS test will not be done. If HI indicates a short-time pGrzB improvement, HS considers a pGrzB increase between days 0 and 24 weeks (± 1 week). If both tests indicate improvements it will be concluded improved & sustained pGrzB response follows sorafenib.

  • Proportion of cluster of differentiation (CD)8+ T cells expressing granzyme B [ Time Frame: Up to 24 weeks ]

Estimated Enrollment: 30
Actual Study Start Date: November 18, 2013
Estimated Study Completion Date: August 3, 2018
Estimated Primary Completion Date: August 3, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (sorafenib tosylate)
Patients receive sorafenib tosylate PO BID. Treatment continues in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Sorafenib Tosylate
Given PO
Other Names:
  • BAY 43-9006 Tosylate
  • BAY 54-9085
  • Nexavar
  • sorafenib

Detailed Description:


I. To determine whether the proportion of cytotoxic T lymphocytes that are producing granzyme B (denoted pGrzB) as measured ~28-35 days after initiation of sorafenib (sorafenib tosylate) therapy correlates with overall survival, defined as the number of months between the start of sorafenib treatment and death from any cause.


I. To determine whether higher pGrzB levels will correlate with better sorafenib tolerance, manifested by fewer dose reductions, dose interruptions and adverse events.

II. To determine whether improved immune function may also result in greater recognition of hepatitis viral antigens.


Patients receive sorafenib tosylate orally (PO) twice daily (BID). Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study, patients are followed up for 30 days or after the 6 month time point if continuing sorafenib tosylate and then periodically thereafter.


Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Subject or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
  • Outpatients with histologically/cytologically documented or radiographically diagnosed unresectable hepatocellular carcinoma (HCC) who are candidates for systemic therapy and for whom a decision to treat with sorafenib has been made; radiographic diagnosis needs typical findings of HCC by a radiographic method, i.e. on multi-dimensional dynamic computed tomography (CT), CT hepatic arteriography (CTHA)/CT arterial portography (CTAP) or magnetic resonance imaging (MRI)
  • Patients must have a life expectancy of at least 8 weeks
  • Patients must not have any evidence of bleeding diathesis or active gastrointestinal bleeding

Exclusion Criteria:

  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant or nursing female subjects
  • Unwilling or unable to follow protocol requirements
  • Any condition which in the investigator's opinion deems the subject an unsuitable candidate to receive study drug
  • Patients who have had prior anti-angiogenic therapy, including but not limited to sorafenib, brivanib, bevacizumab, or sunitinib; prior treatment with liver directed, ablative or surgical therapies will be permitted as long as there is documented progression justifying the need for starting sorafenib therapy
  • No known contraindications to anti-angiogenics such as severe coronary artery disease, recent myocardial infarction or stroke within 6 months, bleeding peptic ulcer or varices within last 3 months, and any other major illness that may jeopardize study treatment or follow up
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT02072486

United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Roswell Park    877-275-7724   
Principal Investigator: Renuka V. Iyer         
Sponsors and Collaborators
Roswell Park Cancer Institute
National Cancer Institute (NCI)
Principal Investigator: Renuka Iyer Roswell Park Cancer Institute
  More Information

Responsible Party: Roswell Park Cancer Institute Identifier: NCT02072486     History of Changes
Other Study ID Numbers: I 238913
NCI-2014-00180 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I 238913 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( US NIH Grant/Contract Award Number )
Study First Received: February 24, 2014
Last Updated: April 13, 2017

Additional relevant MeSH terms:
Liver Neoplasms
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Growth Substances
Physiological Effects of Drugs processed this record on April 28, 2017